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Gene deletion of dopamine -hydroxylase and ₁-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling

¹Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7545; ²Institut de Pharmacologie et Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland; ³Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and ⁴Department of Molecular and Cellular Pharmacology, National Children's Medical Research Center, Tokyo 606-8501, Japan

Submitted 25 March 2004 ; accepted in final form 25 June 2004

In vitro studies have shown that stimulation of ₁-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine -hydroxylase (DBH^–/–)] or deficient in ₁-AR subtypes expressed in murine carotid (_1B-AR^–/– and _1D-AR^–/–) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH^–/– and _1B-AR^–/– mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50–91%, resulting in restoration of wall tension to nearly normal (DBH^–/–) or normal (_1B-AR^–/–). In contrast, in _1D-AR^–/– mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH^–/– mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by _1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.

adrenergic receptors; knockout; smooth muscle; adventitia; growth; injury

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